Pituitary growth hormone (GH) is an anabolic protein which promotes growth of tissue and is involved in the regulation of other phases of protein metabolism as well as fat, carbohydrate, and mineral metabolism. Growth hormones from various species differ in their antigenicities, in the range of animals in which they can produce biological responses, in their isoelectric points, N-terminal and C-terminal amino acid residues and amino acid composition. Their molecular weights range from 21,500 for human growth hormone (HGH), to 47,400 for bovine growth hormone. Any growth hormone appears to demonstrate a degree of species-specificity. It is known, however, the humans respond to growth hormone of human or monkey origin.
Growth hormone has been isolated from bovine anterior pituitary, Li, et al., J. Biol. Chem. 159, 353 (1945); Wilhelmi et al., J. Biol. Chem. 176 735 (1948); Li, U.S. Pat. No. 3,118,815 (1964). Human growth hormone has been isolated from human pituitary, Lewis et al., U.S. Pat. No. 2,974,088 (1961); Reisfeld, et al., Endocrinology 71, 559 (1962). Until very recently, isolation of HGH from human cadaver pituitary was the only source for the protein. Accordingly, lack of available material was a primary deterrent for the continuing investigation and definition of therapeutic roles for HGH.
Recently, however, a practical method for synthesizing biologically active growth hormone via recombinant DNA technology has been developed, The Medical Letter, vol. 27, 101-102 (1985). Further, recombinant HGH has now been approved by the Food and Drug Administration for use in humans. See, for example, Genetic Engineering News, Vol. 5, No. 10, pp 1,8 (1985).
Growth hormone plays a prominent role in protein metabolism and the regulation of growth. This is accomplished by accelerating the rate of transfer of amino acids from the extracellular to the intracellular compartment and incorporating the transferred amino acids into cell proteins. Evidence that growth hormone stimulates the synthesis of messenger RNA, ribosomal RNA, and transfer RNA in liver has led to the hypothesis that growth hormone promotes protein synthesis via gene activation. See PHYSIOLOGY, Third Edition, Edited by Selkurt, Little, Brown and Company, page 730 (1971). The overall effect of growth hormone on protein metabolism is evident in the well-documented increase in linear growth resulting from the administration of growth hormone to GH-deficient dwarves, It has been shown that this increase in body cell mass (as reflected by total body potassium) is at the expense of adipose tissue. Collipp, T. J. et al., Metabolism 2214, 589-595 (1973).
Similar changes in burn patients treated with growth hormone have been demonstrated as well. Soroff, H. S. et al., Ann. Surg. 166, 739-752 (1967). Metabolic studies on normal subjects have consistently shown overall retention of nitrogen and potassium as well as other cellular constituents upon administration of growth hormone. Beck, J. C. et al., Metabolism 8, 699-737 (1960); Bergenstall, D. M., et al., J. Clin. Endo. and Metab., 20-11, 1427-1436 (1960); and MRC Panel, Lancet, 1, 7-12 (1959). The action of growth hormone in stressed states has been studied extensively in burned patients. Prudden et al. administered bovine growth hormone to four burned patients and demonstrated an anabolic effect dependent on food intake; growth hormone only improved nitrogen balance at high levels of nitrogen intake. Below a certain level of nitrogen intake it appeared to have a deleterious effect, resulting in a worse balance of nitrogen and essential elements. Surg. Gyn. Obs., 102, 695-701 (1956). Burned rats receiving adequate nutrition and growth hormone did not sustain a catabolic response, but when the burned rats were starved, they lost weight at a greater rate than controls. Gump, F. E. et al., Am. J. Med. Sci., 239, 27-32 (1960). Based on this observation, Gump et al. proposed the "critical point" hypothesis which states that "adequate" calories and nitrogen are necessary for growth hormone to exert its anabolic effect. This hypothesis was reinforced by the work of Felig, P. et al., J. Clin. Invest., 50, 411-421 (1971) who administered growth hormone to fasting, obese volunteers and reported reduction in urea excretion which was associated with marked ketoacidosis. This acidosis resulted in increased renal ammonia generation and excretion so that net nitrogen loss was unchanged from previous control periods.
Soroff, H. S. et al., Surg. Gyn. Obs., 111, 259-273 (1960), working with burned patients, was unable to show a beneficial effect from administration of bovine growth hormone. The same authors did show a positive effect in similar study using human growth hormone during the anabolic phase of burn recovery. Ann. Surg., 166, 739-752 (1967). Liljedhal, S. et al., Acta. Char. Scand., 122, 1-14 (1961) and Wilmore, D. W. et al., Surg. Gyn. Obs., 138, 875-884 (1973) demonstrated significant improvement in nitrogen and potassium balance in the post-burn period, the latter specifically with high calorie and protein intake. Moreover, a mood-elevating and appetite stimulating effect was reported which, in the Liljedhal et al. study where ad libitum intake was allowed, led to greater substance intake.
Roe, C. F. et al., Surg. Forum, 13, 369-371 (1962), demonstrated an alteration in substrate utilization in postoperative orthopedic patients given growth hormone, with a fall in respiratory quotient (RQ) and a shift to lipid substrates. Johnston, R. D. A. et al., Lancet, 584-586 (Mar. 16, 963) showed no improvement in nitrogen balance after herniorrhaphy in patients treated with growth hormone and in matched controls. However, nitrogen intakes were low, caloric provisions were not measured, and only the immediate postoperative period was studied.
Administration of growth hormone to postoperative patients receiving only 5% dextrose has been described by Ward, H. C. et al., in an abstract presented at the Annual European Society of Enteral and Parenteral Nutrition, Abstract Book No. 0.24 (September 1984). The individuals studied excreted less nitrogen and had lower respiratory quotients than the placebo-matched controls. Ward et al. investigated the effect of human GH treatments (0.1 mg/kg/day) given in conjunction with hypocaloric (400 kcals as 2 liters of 5% dextrose/day) peripheral intravenous infusion. No amino acid supplement was present in the feedings.
Dietary control of the nitrogen balance has been studied as well. Howard, U.. Pat. No. 4,009,265, disclosed formulations for the treatment of obesity, describing the use of a low calorie (160-600 Kcal.) diet containing 15-75 grams of amino acids per day to prevent nitrogen loss. Howard, U.S. Pat. No. 4,298,601, described a diet for maintaining nitrogen balance and controlling ketosis and water retention. The daily intake comprised at least 15 grams of amino acids, in the proportion required by humans, and from 15-75 grams of carbohydrates, with a total caloric value of 160-600 kcals. Dietz et al., U.S. Pat. No. 4,283,392, disclosed infusions for low-calorie parenteral nutrition containing 10-200 grams of essential and non-essential amino acids and 50-10,000 ug of kinin per liter of infusion solution. This infusion mixture was designed to replace approximately 1,000 calories per day. According to Dietz et al., the presence of kinin provided a definite improvement in the amino acid utilization in the sense of a anabolic effect relating to the build-up of body-produced proteins.